key: cord-0821743-pc01enkv
authors: Tazza, F.; Lapucci, C.; Cellerino, M.; Boffa, G.; Novi, G.; Poire, I.; Mancuso, E.; Bruschi, N.; Sbragia, E.; Laroni, A.; Capello, E.; Inglese, M.
title: Personalizing ocrelizumab treatment in Multiple Sclerosis: What can we learn from Sars-Cov2 pandemic?
date: 2021-08-15
journal: J Neurol Sci
DOI: 10.1016/j.jns.2021.117501
sha: d9fa9f2bcc8e4b700e4274f120dda405d1d3e9b0
doc_id: 821743
cord_uid: pc01enkv

During SARS-CoV-2 pandemic, we adopted a personalized delayed protocol for ocrelizumab infusions in Relapsing Remitting Multiple Sclerosis (RRMS) patients according to the national recommendations. Out of the 83 RRMS patients whose infusion was scheduled between March and December 2020, 56 patients experienced a delay in treatment based on MS severity and SARS-CoV2 infection risk profile. In most cases, the immunophenotype was performed monthly to guide re-infusions. Specifically, B CD19 + cells repopulation rate was monitored. Mean infusion delay was 103,1 [SD 40,6] days, and none of the patients presented relapses or active disease at MRI at the end of the observation period. Treatment naïve status and the interval between immunophenotyping and the last ocrelizumab infusion were predictors of earlier B CD19 + cells repopulation. Two patients contracted SARS-CoV2 with complete recovery. Definitive data about Sars-Cov2 vaccine efficacy in patients treated with ocrelizumab are still lacking. Our findings suggest that a personalized treatment with a delayed infusion schedule does not compromise ocrelizumab short-term efficacy and may help to lengthen the therapeutic window for an effective response to SARS-CoV2 vaccine.

CD19 + cells repopulation. Two patients contracted SARS-CoV2 with complete recovery. Definitive data about Sars-Cov2 vaccine efficacy in patients treated with ocrelizumab are still lacking. Our findings suggest that a personalized treatment with a delayed infusion schedule does not compromise ocrelizumab short-term efficacy and may help to lengthen the therapeutic window for an effective response to SARS-CoV2 vaccine.

 Brief postponing of Ocrelizumab infusions appears to not impact on short-term efficacy and safety outcomes.

 CD19+ cells monitoring may help to guide re-infusion timing in patients with RRMS, preserving the efficacy of treatment against MS inflammatory activity  Treatment naïve RRMS patients seems to present a faster repopulation rate in comparison with previously treated RRMS patients.

 A positive correlation was found between CD19+ cells repopulation rate and the time interval from last ocrelizumab infusion date. The aim of this study was to investigate the effect of delayed ocrelizumab infusions on clinical, radiological and immunological outcomes in a cohort of patients with relapsing-remitting MS.

In this retrospective study, we identified 83 RRMS patients whose treatment with Ocrelizumab were scheduled between 1st March 2020 and 1st December 2020.

J o u r n a l P r e -p r o o f

For 56 RRMS patients included in this cohort, we decided to delay ocrelizumab infusion. Delay in treating with ocrelizumab was personalized for each patient, considering MS severity and the risk of developing severe COVID-19 related complications. With regard to MS severity, we identified "aggressive MS" patients [5] , as patients showing MRI activity and at least one relapse in the year before ocrelizumab start associated with accelerated accrual of disability (EDSS>=4.0). Of the remaining patients, those who did not present clinical activity after ocrelizumab start were defined "clinically stable". Age and cardiovascular comorbidities were evaluated for each patient and considered to outline the individual risk profile related to COVID19 infection.

In Fig.1 , we reported the whole cohort of patients involved in the study, including patients who did not experienced any delay in ocrelizumab treatment in the abovementioned timeframe and the reasons of this therapeutic choice.

More specifically:

-from March to April 2020 (first pandemic wave), ocrelizumab was administered only to patients with "aggressive MS" who had to complete induction cycle or to perform the first maintenance infusion.

-at the end of April 2020 (when pandemic wave was slowly decreasing), treatment administration was reintroduced. In this phase, the majority of patients performed immunophenotype (IP) monthly and were managed as follows:

 RRMS patients with "aggressive MS" whose maintenance infusions had been delayed were reinfused as soon as possible regardless of IP findings.

 "Clinically stable" RRMS patients who received ocrelizumab re-infusion when the B CD19+ cell population reached the cut-off of 1% of total lymphocyte count. [6] [7] Then, we decided to use a conservative approach and patients whose infusion would have been delayed for more than 3 months, were re-treated, regardless of the B CD19+ cells count.

When possible, 3T brain MRI (Prisma, Siemens) was planned before ocrelizumab re-infusion.

Data about relapses, Expanded Disability Status Scale (EDSS) progression and MRI activity before the ocrelizumab infusion were acquired. Adverse events (AEs) were also recorded. Analyses were performed using SPSS 22.0 (IBM; X). Distribution of data were analyzed using Kolmogorov Smirnov test.

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were assessed using Chi-Square test, independent samples t-test, Mann-Whitney test as appropriate.

Correlations between demographic and clinical variables and the evidence of B CD19+ cells repopulation was explored using binary logistic regression analyses adjusted for age, sex and BMI. All p values were 2sided and considered statistically significant when p ≤ 0.05.

All patients involved in the study signed the informed consent. The study was approved by the Local Ethic Committee.

Demographic and clinical features of the 83 RRMS patients whose treatment with ocrelizumab was scheduled between March and December 2020 are reported in Table 1 and Fig. 1 .

Fifty-six RRMS patients (67.4%) experienced a delay in ocrelizumab infusion, while for 27 RRMS patients (32.6%) the treatment was regularly performed.

With regard to patients who had a delay in ocrelizumab treatment, 5 (8.9%) were patients who fulfilled the criteria of "aggressive MS"; these patients were re-treated as soon as possible (May 2020), regardless of IP findings. The remaining 51 RRM patients (91%) were "clinically stable" and received ocrelizumab reinfusion when the B CD19+ cell population reached the cut-off of 1% of total lymphocyte count.

Of the 56 RRMS patients who experienced a delay, no patients showed clinical relapses or confirmed disability progression during the delay period.

Thirty-three (58.9%) patients performed 3T brain MRI before the delayed ocrelizumab re-infusion. No patients showed gadolinium enhancing lesions; 2 patients presented 1 new T2 lesion. In this scenario, in addition to rapid infusion protocols implementation [10] , our MS centre adopted a personalized infusion schedule based on MS severity and the risk of developing severe COVID-19 related complications. In particular, we decided to delay ocrelizumab treatment in 56 of the 83 RRMS patients whose infusion was scheduled between March and December 2020. With the exception of "aggressive MS" patients who were re-treated immediately after the first pandemic wave regardless of IP findings, for the remaining patients (51/56, 91%) the evidence of B CD19+ cells repopulation guided the re-infusions time schedule. No patients showed relapses nor disability progression during the delay, in line with a recent study performed in a smaller cohort [11] . Furthermore, none of the patients who performed brain MRI before the delayed re-infusions showed active lesions. Two patients presented a new T2 lesion. Nevertheless, it was not possible to rule out if they had developed due to the delay, because the previous MRIs (used for comparison) had been performed 1 year and 9 months before the lockdown, respectively.

In our cohort, a 7-fold increase of the probability of B CD19+ cells repopulation within 3 months of delay was observed in treatment naïve patients. Moreover, the time interval between IP and last ocrelizumab infusion date was a significant predictor [6] of B CD19+ cells repopulation within 3 months of delay while a trend was found for the number of ocrelizumab infusion at the delay.

Moreover, the efficacy of a tailored infusion regimen has been previously demonstrated in patients treated with rituximab [12] and ocrelizumab [13] . Guided by the findings obtained in patients treated with rituximab for MS [6] and neuromyelitis optica spectrum disorder [14] , we used the threshold of 1% of B CD19+ cells to guide re-infusions. Although a long-lasting delay [12] [13] have demonstrated to provide a good disease control, we chose to adopt a more conservative approach, not exceeding 3 months of delay from the last ocrelizumab infusion. The evidence of an earlier B cell repopulation in some patients and the lack of definitive data about the impact of delaying ocrelizumab on disability progression guided our therapeutic choice.

In line with previous findings [6, 12, 13] , our results should prompt the design of prospective studies based on B cells repopulation. Furthermore, the possible interfering activity of anti-CD20 treatments on the response to vaccines is a well-known issue in clinical practice [15] although definitive data about Sars-Cov2 vaccine efficacy in patients treated with ocrelizumab are still lacking. In the meanwhile, a safe and personalized ocrelizumab treatment with a delayed infusion schedule may help to lengthen the therapeutic window and increase the possibility to obtain an effective humoral response to SARS-CoV2 vaccine.

This study did not receive any funding support. 

Not applicable

Not applicable

This study was approved by local ethical committee

All patients signed a written informed consent concerning the publication of the data included in this paper. J o u r n a l P r e -p r o o f

Extending rituximab dosing intervals in patients with MS during the COVID-19 pandemic and beyond? Neurol Neuroimmunol Neuroinflamm

Fast and safe: Optimising multiple sclerosis infusions during COVID-19 pandemic

Influence of delaying ocrelizumab dosing in multiple sclerosis due to COVID-19 pandemics on clinical and laboratory effectiveness

B-cell depletion with rituximab in relapsing-remitting multiple sclerosis

The ocrelizumab phase II extension trial suggests the potential to improve the risk: Benefit balance in multiple sclerosis

A 5-year follow-up of rituximab treatment in patients with neuromyelitis optica spectrum disorder JAMA Neurol

COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases